Medical articles having surfaces designed to prevent or inhibit thrombus formation are known in the art. The need for such surfaces has become increasingly important due to the common use of polymeric implants in areas of the body where contact with moving blood is required, e.g., heart, blood vessels. Numerous other medical articles formed from polymeric materials, such as catheters, tubing in heart-lung machines, and tubing and membranes in kidney dialysis machines require contact with blood. The contact sites on the surface of untreated polymeric articles are prone to thrombus formation due to improper protein deposition on the surface of the polymeric article and to platelet adhesion and subsequent aggregation. Such thrombi may serve as a source of emboli which are potentially life-threatening.
Heparin is known to prolong the clotting time of blood. Several techniques are described in the art for appending heparin to polymeric devices and films to reduce thrombus formation on the surfaces thereof. U.S. Pat. No. 3,441,142 discloses a permeable membrane wherein the alkali metal salt of heparin reacts with a polymer containing a quaternized nitrogen moiety. U.S. Pat. No. 3,755,218 discloses a nonthrombogenic reaction product between a polyquaternary polyurethane and heparin, and U.S. Pat. No. 3,932,627 teaches the heparinization of polymeric surfaces with a silver-heparin-allantoin complex. U.S. Pat. No. 3,475,410 discloses the amination of cellulose film and its subsequent heparinization to produce a nonthrombogenic surface thereon. R. Evans and others, Thrombos. Haemostas., 41, 537 (1979) disclose partial prevention of intravascular thrombus formation on plastic catheters surface-treated with a heparin-benzalkonium complex.
Although the heparin-treated surfaces described in the prior art are generally successful in reducing thrombus formation to some degree, there still existed, prior to the present invention, the need for an improved method of attaching an antithrombogenic agent to a polymeric surface which would substantially eliminate thrombus formation. According to the present invention, it has been discovered that by using an intermediate layer of chitosan to bond an antithrombotic agent such as heparin to the polymeric substrate, the surface exhibits surprisingly improved antithrombogenic character over other heparin-treated surfaces.
Chitosan complexes with heparin and other sulfated polysaccharides have been reported in the literature. Y. Kikuchi and A. Noda, J. of Applied Polymer Science, 20, 2561 (1976) have studied water-insoluble polyelectrolyte complexes of heparin with chitosan. The antithrombogenic character of the polyelectrolyte complexes is under investigation. A glycol chitosanheparin complex, stoichiometrically formed, is disclosed by A. Nakagima and K. Shinoda, J. of Colloid and Interface Science, 55, No. 1, 126 (1976), although no use is specified. Yasuo Kikuchi and Tatsuko Toyota, Hiroshima Daigaku Kogakubn Kenkyn Hokoku 24(2), 7-9 (1976), abstract available, CA 85: 10389C, disclose polyelectrolyte complexes of chitosan and sodium dextran sulfate, which, like heparin, is a sulfated polysaccharide, and which are antithrombogenic.
The above-mentioned complexes when formed are insoluble in water and common organic solvents and would not render themselves amenable to a coating process. Hence, the above-mentioned chitosan complexes and their methods of formation are different in character and not useful for preparing the layered composite structures disclosed herein which provide antithrombogenic surfaces to medical articles. Applicants rely on uncomplexed chitosan as a coating which is subsequently subjected to bonding with an antithrombogenic agent. Disclosed herein are composite structures which are blood compatible and which maintain their efficacy for longer periods of time than can be achieved with prior art materials.